Axotomy-induced changes in the neuronal cell body, surrounding glia, and proximal axon are collectively termed the axotomy response. A prominent component of this response is the reordering of gene expression for several neuronal proteins involved in axonal growth. These changes include a decline in the abundance of mRNAs encoding the neurofilament proteins and increases in the expression of the class II isotype of beta tubulin and GAP-43. One goal of the proposed studies is to identify regulatory sequences in neuronal genes which are required for these axotomy-induced changes in expression. This will be accomplished by determining whether appropriate gene constructs in transgenic mice are subject to axotomy-induced changes in expression. Another goal of the proposed studies is to determine whether components of the axotomy response are regulated by different physiological signals. In theory, the axotomy response could be initiated by signals originating from several potential sources, including target cells, the neuron itself, ensheathing Schwann cells, and the distal stump. At least for the first three candidates, the signal could either involve loss of a factor normally produced and carried back to the cell body (by retrograde axonal transport), or the appearance of a new injury-related signal. In these studies we will first determine whether components of the axotomy response can be dissociated by either varying the location (proximal or distal) of axonal injury or by impaired degeneration of the distal stump. We will then determine whether perturbations in the physiology of the axon, neuromuscular junction or muscle induced by local application of specific neurotoxins produce changes similar to those which occur after axotomy. If they do, we will determine whether these toxin-induced changes in gene expression involve the same gene regulatory sequences as axotomy-induced changes.